DePalma was immediately successful in car racing. In 1911, DePalma won the first Milwaukee Mile[4] Championship Car race. However, he is still remembered for the dramatic manner in which he lost the 1912 Indianapolis 500. After leading the race for 196 of the 200 laps, his Mercedes cracked a piston and with only 2 laps remaining; he and his mechanic had to push the car across the finish line to take eleventh place.[3] At that time, only cars completing the full 200 laps received any prize money. This Mercedes remains on display at the Indianapolis Motor Speedway Hall of Fame Museum.

He went on to earn the U.S. national driving championship that year,[1] but was almost killed in an accident at on October 5 at the Grand Prize held in a road course in Milwaukee. After being impaled by a corn stalk, he was hospitalized for 11 weeks;[2] he recovered and was back to racing the following spring.

DePalma had been let go by the Mercer Automobile Co. racing team in favor of Barney Oldfield.[1] In a Mercedes "Gray Ghost," he showed he was a master tactician in beating Oldfield's much faster car.[3] He ended 1914 by winning his second U.S. national driving championship.[1] The following year, 1915, he drove to victory at 1915 Indianapolis 500 with a Mercedes 4.5 liter Gp car.

DePalma was an intense competitor but one of the most popular racers with his fellow drivers and the fans because of his good sportsmanship, a quality he displayed on and off the track. In June 1917 he lost to Barney Oldfield in a series of 10 to 25 mile match races at the Milwaukee Mile. On February 12, 1919 at Daytona Beach, Florida, he drove a Packard to a world speed record of 149.875 mph (241.200 km/h) over a measured mile (1.6 km).[3] International competition began following the adoption of the three liter engine limit in the U.S. and Europe in 1920. DePalma began the year driving for the French manufacturer, Ballot. His Ballot vehicle won the pole position for the 1920 Indy race[5] and he led for many laps[5] but bad luck dogged him in the race (faulty bearings on the Ballot) and he did not finish.[5] However, DePalma did race his Ballot vehicle in the Elgin Road Race and won his third Elgin trophy in 1920. Then in 1921 DePalma traveled with other Americans to Le Mans to compete in the French Grand Prix. There, he finished second to the Duesenberg driven by fellow American, Jimmy Murphy. DePalma won the Canadian national championship in 1929.[3]

DePalma later competed in stock cars until he retired from racing in 1936.[1] In his career, he competed in 2,889 races in America and Europe and won 2,557, according to his Associated Press obituary that appeared in the Detroit Free Press on April 1, 1956.[2] He was an honorary referee for the Indianapolis 500, the last time in 1954.[3]

Ralph DePalma had a small role in the 1920 Hollywood film, High Speed and in 1924 played the part of the Champion in an action/drama written by Wilfred Lucas titled Racing for Life. In 1923, he established the DePalma Manufacturing Company in Detroit to build race cars and engines for automobiles and aircraft.

DePalma was the brother of 500 competitor John DePalma[8] and the uncle of 1925 Indy winner Peter DePaolo.[9] De Palma obtained his American citizenship in 1920 (available at[10]), and as such he is considered the second non-American driver to win the Indianapolis 500 after Jules Goux.